RESUMEN
Much attention has been focused on the catalytic asymmetric creation of single chiral centers or two adjacent stereocenters. However, the asymmetric construction of two nonadjacent stereocenters is of significant importance but is challenging because of the lack of remote chiral induction models. Herein, based on a CâC bond relay strategy, we report a synergistic Pd/Cu-catalyzed 1,5-double chiral induction model. All four stereoisomers of the target products bearing 1,5-nonadjacent stereocenters involving both allenyl axial and central chirality could be obtained divergently by simply changing the combination of two chiral catalysts with different configurations. Control experiments and DFT calculations reveal a novel mechanism involving 1,5-oxidative addition, contra-thermodynamic η3-allyl palladium shift, and conjugate nucleophilic substitution, which play crucial roles in the control of reactivity, regio-, enantio-, and diastereoselectivity. It is expected that this CâC bond relay strategy may provide a general protocol for the asymmetric synthesis of structural motifs bearing two distant stereocenters.
RESUMEN
The first aerobic protocol of direct transformation of p-methoxybenzyl (PMB) ethers to carboxylic acids efficiently with Fe(NO3)3â¢9H2O and TEMPO as catalysts at room temperature has been developed. The reaction accommodates C-Br bond, terminal/non-terminal C-C triple bond, amide, cyano, nitro, ester, and trifluoromethyl groups, etc. Even highly selective oxidative deprotection of different benzylic PMB ethers has been realized. The reaction has been successfully applied to the total synthesis of natural product, (R)-6-hydroxy-7,9-octadecadiynoic acid, demonstrating the practicality of the method. Based on experimental studies, a possible mechanism involving oxygen-stabilized benzylic cation has been proposed.
RESUMEN
Porcine reproductive and respiratory syndrome virus (PRRSV) is a severe disease with substantial economic consequences for the swine industry. The DEAD-box helicase 3 (DDX3X) is an RNA helicase that plays a crucial role in regulating RNA metabolism, immunological response, and even RNA virus infection. However, it is unclear whether it contributes to PRRSV infection. Recent studies have found that the expression of DDX3X considerably increases in Marc-145 cells when infected with live PRRSV strains Ch-1R and SD16; however, it was observed that inactivated viruses did not lead to any changes. By using the RK-33 inhibitor or DDX3X-specific siRNAs to reduce DDX3X expression, there was a significant decrease in the production of PRRSV progenies. In contrast, the overexpression of DDX3X in host cells substantially increased the proliferation of PRRSV. A combination of transcriptomics and metabolomics investigations revealed that in PRRSV-infected cells, DDX3X gene silencing severely affected biological processes such as ferroptosis, the FoxO signalling pathway, and glutathione metabolism. The subsequent transmission electron microscopy (TEM) imaging displayed the typical ferroptosis features in PRRSV-infected cells, such as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and cytoplasmic membrane rupture. Conversely, the mitochondrial morphology was unchanged in DDX3X-inhibited cells. Furthermore, silencing of the DDX3X gene changed the expression of ferroptosis-related genes and inhibited the virus proliferation, while the drug-induced ferroptosis inversely promoted PRRSV replication. In summary, these results present an updated perspective of how PRRSV infection uses DDX3X for self-replication, potentially leading to ferroptosis via various mechanisms that promote PRRSV replication.
Asunto(s)
ARN Helicasas DEAD-box , Ferroptosis , Virus del Síndrome Respiratorio y Reproductivo Porcino , Replicación Viral , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Animales , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Ferroptosis/fisiología , Porcinos , Síndrome Respiratorio y de la Reproducción Porcina/virología , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Línea CelularRESUMEN
Rural waste accumulation leads to heavy metal soil pollution, impacting microbial communities. However, knowledge gaps exist regarding the distribution and occurrence patterns of bacterial communities in multi-metal contaminated soil profiles. In this study, high-throughput 16â¯S rRNA gene sequencing technology was used to explore the response of soil bacterial communities to various heavy metal pollution in rural simple waste dumps in karst areas of Southwest China. The study selected three habitats in the center, edge, and uncontaminated areas of the waste dump to evaluate the main factors driving the change in bacterial community composition. Pollution indices reveal severe contamination across all elements, except for moderately polluted lead (Pb); contamination severity ranks as follows: Mn > Cd > Zn > Cr > Sb > V > Cu > As > Pb. Proteobacteria, Actinobacteria, Chloroflexi, and Acidobacteriota predominate, collectively constituting over 60% of the relative abundance. Analysis of Chao and Shannon indices demonstrated that the waste dump center boasted the greatest bacterial richness and diversity. Correlation data indicated a predominant synergistic interaction among the landfill's bacterial community, with a higher number of positive associations (76.4%) compared to negative ones (26.3%). Network complexity was minimal at the dump's edge. RDA analysis showed that Pb(explained:46%) and Mn(explained:21%) were the key factors causing the difference in bacterial community composition in the edge area of the waste dump, and AK(explained:42.1%) and Cd(explained:35.2%) were the key factors in the center of the waste dump. This study provides important information for understanding the distribution patterns, co-occurrence networks, and environmental response mechanisms of bacterial communities in landfill soils under heavy metal stress, which helps guide the formulation of rural waste treatment and soil remediation strategies.
Asunto(s)
Metales Pesados , Microbiología del Suelo , Contaminantes del Suelo , Suelo , Metales Pesados/análisis , Metales Pesados/toxicidad , Contaminantes del Suelo/análisis , Contaminantes del Suelo/toxicidad , China , Suelo/química , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/clasificación , ARN Ribosómico 16S , Instalaciones de Eliminación de Residuos , Monitoreo del Ambiente , Proteobacteria , Actinobacteria/genética , Microbiota/efectos de los fármacos , Chloroflexi/efectos de los fármacos , Chloroflexi/genéticaRESUMEN
Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.
RESUMEN
CD1E, one of the most important glycolipid antigens on T cell membranes, is required for glycolipid antigen presentation on the cell surface. Cell-based recombinant expression systems have many limitations for synthesizing transmembrane proteins such as CD1E, including low protein yields and miss folding. To overcome these challenges, here we successfully synthesized high-quality soluble CD1E using an E.coli cell-free protein synthesis system (CFPS) with the aid of detergent. Following purification by Ni2+ affinity chromatography, we were able to obtain CD1E with ≥90% purity. Furthermore, we used the string website to predict the protein interaction network of CD1E and identified a potential binding partnerâB2M. Similarly, we synthesized soluble B2M in the E.coli CFPS. Finally, we verified the interaction between CD1E and B2M by using Surface Plasmon Resonance (SPR). Taken together, the methods described here provide an alternative way to obtain active transmembrane protein and may facilitate future structural and functional studies on CD1E.
Asunto(s)
Glucolípidos , Proteínas de la Membrana , Glucolípidos/metabolismo , Proteínas de la Membrana/metabolismo , Membrana Celular/metabolismo , Sistema Libre de Células/metabolismoRESUMEN
In cluster research, determining the ground-state structure of medium-sized clusters is hindered by a large number of local minimum on potential energy surfaces. The global optimization heuristic algorithm is time-consuming due to the use of DFT to determine the relative size of the cluster energy. Although machine learning (ML) is proved to be a promising way to reduce the DFT computational costs, a suitable method to represent clusters as input vectors is one of the bottlenecks in the application of ML to cluster research. In this work, we proposed a multiscale weighted spectral subgraph (MWSS) as an effective low-dimension representation of clusters and build an MWSS-based ML model to discover the structure-energy relationships in lithium clusters. We combine this model with the particle swarm optimization algorithm and DFT calculations to search for globally stable structures of clusters. We have successfully predicted the ground-state structure of Li20.
RESUMEN
An efficient double allene protocol for the formation of benzazocines has been developed. The reaction constitutes a highly regioselective palladium-catalyzed formal [6+2] annulation of allenyl benzoxazinanones with terminal allenes forming the challenging 8-membered cycles. Decent yields and excellent regioselectivity have been observed under mild conditions with a remarkable Z-stereoselectivity for the exo-cyclic C=C bonds. The synthetic potentials of benzazocine products have been demonstrated.
RESUMEN
The stereodivergent synthesis of allene compounds bearing α,ß-adjacent central chiralities has been realized via the Pd/Cu-catalyzed dynamic kinetic asymmetric alkylation of racemic allenylic esters. The matched reactivity of bimetallic catalytic system enables the challenging reaction of racemic aryl-substituted allenylic acetates with sterically crowded aldimine esters smoothly under mild reaction conditions. Various chiral non-natural amino acids bearing a terminal allenyl group are easily synthesized in high yields and with excellent diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). Importantly, all four stereoisomers of the product can be readily accessed by switching the configurations of the two chiral metal catalysts. Furthermore, the easy interconversion between the uncommon η3 -butadienyl palladium intermediate featuring a weak C=C/Pd coordination bond and a stable Csp2 -Pd bond is beneficial for the dynamic kinetic asymmetric transformation process (DyKAT).
RESUMEN
Many terpenoids with isoprene unit(s) demonstrating critical biological activities have been isolated and characterized. In this study, we have developed a robust chem-stamp strategy for the construction of the key isoprene unit, which consists of two steps: one-carbon extension of aldehydes to the alkenyl boronates by the boron-Wittig reaction and the rhodium-catalyzed reaction of alkenyl boronates with 2,3-allenols to yield enals. This chem-stamp could readily be applied repeatedly and separately, enabling the modular concise synthesis of many natural and pharmaceutically active terpenoids, including retinal, ß-carotene, vitamin A, tretinoin, fenretinide, acitretin, ALRT1550, nigerapyrone C, peretinoin, and lycopene. Owing to the diversified availability of the starting materials, aldehydes and 2,3-allenols, creation of new non-natural terpenoids has been realized from four dimensions: the number of isoprene units, the side chain, and the two terminal groups.
Asunto(s)
Hemiterpenos , Terpenos , Butadienos , Aldehídos/química , CatálisisRESUMEN
The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.
RESUMEN
Chiral organophosphorous compounds are very important in catalysis, organic syntheses, and medicinal chemistry. However, catalytic enantioselective protocols for the axially chiral allenyl phosphorus compounds have never been reported. Herein, a palladium-catalyzed enantioselective carbon-phosphorus bond formation reaction affording axially chiral allenyl phosphonates has been developed. The reaction enjoys high yields and ees accommodating a wide range of functional groups. Mechanistic studies have unveiled an overwhelming kinetic resolution process.
Asunto(s)
Paladio , Catálisis , Técnicas de Química Sintética/métodos , Paladio/química , EstereoisomerismoRESUMEN
Rh-catalyzed dynamic kinetic intramolecular [4+2] cycloaddition reaction of 1,3-disubstituted allene-1,3-dienes afforded cis-fused [4.3.0]bicyclic products with an excellent chemo-, diastereo-, and enantio-selectivity. Many synthetically useful functional groups are tolerated. The synthetic utility has been demonstrated. Based on the careful experimental studies, a mechanism involving the rapid racemization of the allene moiety in the starting materials has been proposed.
Asunto(s)
Rodio , Reacción de Cicloadición , Estereoisomerismo , Catálisis , Estructura MolecularRESUMEN
Naturally occurring conjugated allenynes are of general interest owing to their potent and various biological activities. The 1,5-H transfer of alka-1,4-diyn-3-yl amines would be one of the most straightforward yet challenging approaches to such compounds since, in principle, two regioisomers may be formed involving two C-C triple bonds. Herein, a catalytic recipe of copper halides with mixed oxidation states, i.e., CuCl/CuBr2 , has been identified to address the issues of the side reaction of conjugate addition and the selectivity of 1,5-H transfer of alka-1,4-diyn-3-yl amines in EATA (enantioselective allenation of terminal alkynes) reaction involving 2-alkynals. This method provided various allenynes with excellent enantioselectivities, and was also applied to the first highly enantioselective total synthesis of natural product scorodonin. Mechanistic studies and DFT calculations elucidated the regioselectivity for the observed 1,5-H transfer.
RESUMEN
In contrast to the widely explored methods for the asymmetric synthesis of molecules bearing a single stereocenter or adjacent stereocenters, the concurrent construction of 1,3-stereogenic centers in an enantio- and diastereoselective manner remains a challenge, especially in acyclic systems. Herein, we report an enantio- and diastereodivergent construction of 1,3-nonadjacent stereocenters bearing allenyl axial and central chirality through synergistic Pd/Cu-catalyzed dynamic kinetic asymmetric allenylation with racemic allenylic esters. The protocol is suitable for a wide range of substrates including the challenging allenylic esters with less sterically bulky substituents and provided chiral allenylic products bearing 1,3-nonadjacent stereocenters with high levels of enantio- and diastereoselectivities (up to >20:1 dr and >99% ee). Furthermore, several representative transformations involving axial-to-central chirality transfer were conducted, affording useful structural motifs containing nonadjacent stereocenters in a diastereodivergent manner.
RESUMEN
A gold-catalyzed room temperature allenation of terminal alkynes (ATA) with aldehydes affording 1,3-disubstituted allenes with diverse functional groups has been developed by identifying a gold(I) catalyst and an amine. The practicality of this reaction has been demonstrated by a ten gram-scale synthesis and the synthetic potentials have been demonstrated via various transformations and formal total synthesis of (-)-centrolobine. Mechanistic studies revealed that the gold catalyst, the aldehyde effect, the fluoroalkyl hydroxyl solvent (TFE or HFIP) and the structure of amine are vital in this room temperature ATA reaction.
RESUMEN
Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.
RESUMEN
So far, over 150 natural products and pharmaceuticals containing an allene moiety have been identified. During the last two decades, allenes have also been demonstrated as synthetically versatile starting materials in organic synthesis. In comparison to alkenes and alkynes, allenes are unique unsaturated hydrocarbons due to their axial chirality, which could be transformed to central chirality via chirality transfer to provide an irreplaceable entry to chiral molecules. Thus, methods for allene synthesis from readily available chemicals are of great interest. In 1979, Crabbé et al. reported the first CuBr-mediated allenation of terminal alkynes (ATA) reaction to form monosubstituted allenes from 1-alkynes and paraformaldehyde in the presence of diisopropylamine. During the following 30 years, the ATA reactions were limited to paraformaldehyde. This Account describes our efforts toward the development of ATA reactions in the last ten years. First, we improved the yields and scope greatly for the synthesis of monosubstituted allenes by modifying the original Crabbé recipe. Next we developed the ZnI2-promoted or CuI-catalyzed ATA reactions for the synthesis of 1,3-disubstituted allenes from terminal alkyne and normal aldehydes. Furthermore, we first realized the CdI2-promoted ATA reaction of ketones with pyrrolidine as the matched amine for the preparation of trisubstituted allenes. Due to the toxicity of CdI2, we also developed two alternative approaches utilizing CuBr/ZnI2 or CuI/ZnBr2/Ti(OEt)4. The asymmetric version of ATA reactions for the synthesis of optically active 1,3-disubstituted allenes has also been achieved in this group with two strategies. One is called "chiral ligand" strategy, using terminal alkynes, aldehydes, and nonchiral amine with the assistance of a proper chiral ligand. The other is the "chiral amine" strategy, applying terminal alkynes, aldehydes, and chiral amines such as ( S)- or ( R)-α,α-diphenylprolinol or ( S)- or ( R)-α,α-dimethylprolinol. Optically active 1,3-disubstituted allenes containing different synthetically useful functionalities such as alcohol, amide, sulfamide, malonate, carboxylate, and carbohydrate units could be prepared without protection with the newly developed CuBr2-catalyzed chiral amine strategy. Recently, we have applied these enantioselective allenation of terminal alkyne (EATA) reactions to the syntheses of some natural allenes such as laballenic acid, insect pheromone, methyl ( R)-8-hydroxyocta-5,6-dienoate, phlomic acid, and lamenallenic acid, as well as some non-allene natural γ-butyrolactones such as xestospongienes (E, F, G, and H), ( R)-4-tetradecalactone, ( S)-4-tetradecalactone, ( R)-γ-palmitolactone, and ( R)-4-decalactone.
RESUMEN
Autophagy is a general protective mechanism for maintaining homeostasis in eukaryotic cells, regulating cellular metabolism, and promoting cell survival by degrading and recycling cellular components under stress conditions. The degradation pathway that is mediated by autophagy receptors is called selective autophagy, also named as xenophagy. Autophagy receptor NDP52 acts as a 'bridge' between autophagy and the ubiquitin-proteasome system, and it also plays an important role in the process of selective autophagy. Pathogenic microbial infections cause various diseases in both humans and animals, posing a great threat to public health. Increasing evidence has revealed that autophagy and autophagy receptors are involved in the life cycle of pathogenic microbial infections. The interaction between autophagy receptor and pathogenic microorganism not only affects the replication of these microorganisms in the host cell, but it also affects the host's immune system. This review aims to discuss the effects of autophagy on pathogenic microbial infection and replication, and summarizes the mechanisms by which autophagy receptors interact with microorganisms. While considering the role of autophagy receptors in microbial infection, NDP52 might be a potential target for developing effective therapies to treat pathogenic microbial infections.
Asunto(s)
Autofagia/fisiología , Infecciones/metabolismo , Proteínas Nucleares/fisiología , Animales , Bacterias/patogenicidad , Citoplasma/metabolismo , Humanos , Infecciones/microbiología , Infecciones/virología , Ubiquitina/metabolismo , Virus/patogenicidadRESUMEN
An efficient pincer-ligand-based cobalt-complex-catalyzed allene hydroboration affording Z-allylic boronates is described. The reaction demonstrates an excellent regio- as well as Z-stereoselectivity and a wide substrate scope that tolerates many functional groups. Based on solvent-assisted electrospray ionization mass spectrometry (SAESI-MS) studies, a rationale for the cobalt-catalyzed hydroboration involving the highly selective insertion of an allene into the Co-H bond to form Z-allylic cobalt intermediates is proposed.